Rett syndrome (RTT) is a severe neurodevelopmental disorder on the autism spectrum that is caused by mutations in the MECP2 gene and affects approximately 1/10,000 female births worldwide. In addition to cognitive, motor and behavioral deficits, one of the most physically debilitating consequences of RTT is severe disruption in the control of breathing, and approximately 25% of RTT patients die prematurely of cardiorespiratory complications. Currently, there are no treatments available for breathing disorders or any other neurological deficit in RTT. To develop effective treatments, it is essentia that we understand how brain circuits that control breathing are disrupted by MECP2 mutations, so that therapeutic targets for restoring normal function can be identified. Therefore, the proposed research will use Mecp2 mutant mice, a well- defined model of RTT to define defects in brain circuit function that perturb normal breathing, including the role of deficits in ribosoma protein S6 (rpS6), a key signaling molecule whose activity is severely decreased in RTT mice. These studies focus in particular on the medial prefrontal cortex (mPFC), a region that we recently found is severely hypofunctional in Mecp2 mutant mice and which is critical for behavioral regulation of breathing, as well as cognitive and other brain functions. We will specifically examine the possibility that reversing circuit defects in the mPFC by interventions that either restore normal levels of neuronal activity or promote synaptic growth and function by increasing rpS6 signaling will reverse respiratory symptoms and other abnormalities in Mecp2 mutants. These studies will include electrophysiological recording in brain slices, physiological and behavioral analyses in intact animals and biochemical and morphological studies of synaptic structure and function, using state-of-the-art chemical-genetic technologies for manipulating the activity of neurons and activity of rpS6 in the mPFC. By defining mechanisms that underlie mPFC dysfunction in Mecp2 mutants, it is hoped these studies will foster development of new therapeutic strategies for breathing disorders and other impairments in RTT patients. Moreover, because mPFC dysfunction is also implicated in non- syndromic autism, our findings may be more broadly applicable to patients on the autism spectrum as a whole.